5-cyano-a-norpregnane-2-one derivatives

ABSTRACT

THIS DISCLOSURE RELATES TO PREGNANES HAVING AN OXYGEN ATOM IN THE 2-POSITION AND A CYANO RADICAL AT THE 5-POSITION. THESE COMPOUNDS POSSESS ANIT-ANDROGENIC ACTIVITY.

United States Patent 3,660,457 -CYANO-A-NURPREGNANE-Z-ONE DERIVATIVES Seymour D. Levine, North Brunswick, Nl, assignor to E. R. Squibb & Sons, Inc., New York, N.Y.

No Drawing. Original application June 19, 1968, Ser. No. 738,091, now Patent No. 3,526,642. Divided and this application May 14, 1970, Ser. No. 48,726

Int. Cl. Ctl7c 121/46 US. Cl. 260464 3 Claims ABSCT OF THE DISCLOSURE This disclosure relates to pregnanes having an oxygen atom in the 2-position and a cyano radical at the 5-pos1- tion. These compounds possess anti-androgenic activity.

This application is a division of S. N. 73 8,091, filed June 19, 1968, now US. Pat. 3,526,642.

This invention relates to pregnanes having the following formula:

wherein R is hydrogen, R is hydroxy, acyloxy or trifluoroacetoxy and together R and R are oxo (0:), wherein the acyl radical is derived from a carboxylic acid, preferably the acyl radical of a hydrocarbon carboxylic acid of less than thirteen carbon atoms, as exemplified by the alkanoic acids (e.'g., acetic, propionic, butyric, enanthic and lauric acid), the alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic and m-toluic acid), the monocyclic aryl lower alkanoic acids (e.g., phenylacetic and [i-phenylpropionic acid), the cycloalkylanecarboxylic acids and the cycloalkenecarboxylic acids.

As anti-androgens, the final products of this invention have been found to be useful in veterinary medicine. Male swine, the meat of which is usually rendered unpalatable by a characteristic odor developed by the mature animal which permeates the meat, may be treated with the final products of this invention in order to suppress the formation of the odor and hence render the meat more palatable. Likewise the caponizing of male chickens may be achieved without resort to castration by means of administration of the final products of this invention. For these purposes, they may be administered orally at a dosage of about 10 to 200 mg./kg. of body weight daily, or parenterally at a dosage of about 2 to 60* mgJkg. of body weight daily.

The end products of this invention may be prepared utilizing either A-norprogesterone or ZOB-hydroxy-A-non pregn-3-en-2-one as starting materials. When utilizing A- norprogesterone as the starting material, it has been found that this material can be selectively reduced to ZOfi-hydroxy-A-norpregn-3-en-2-one by utilizing sodium borohydride or potassium borohydride as the reducing agent at 0 C. These reducing agents selectively reduce the carbonyl at the -position of A-norpregesterone without affecting the oxygen atom at the 2-position.

3,66,457 Patented May 2, 1972 The reduced product is then reacted with potassium cyanide to form a new intermediate of the present invention, 5 3-cyano-2Oil-hydroxy-A-norpregnane-Z-one, which has the formula:

This new intermediate can the be acylated by reacting it with the desired acid anhydride in the presence of an organic base, such as pyridine or it can be subjected to a Baeyer-Villiger reaction to form the new 2-oxa compounds of this invention. Thus, if S/K-cyano-ZOfl-hydroxy- A-norpregnane-Z-one is treated with a peracid, such as peroxytrifluoroacetic acid, the corresponding 2-oxa-5j8- cyano-20fl-trifluoroacetoxypregnane-3-one is obtained. Elf, however, the acyloxy derivative is utilized, the product obtained will be the corresponding 2-oxa-5fl-cyano-20fl-acyloxypregnane-3-one. Hydrolysis of either the acyloxy or trifluoroacetoxy derivatives of this invention will yield the corresponding 20-hydroxy-2-oxa compounds of this invention. The hydrolysis may be carried out by known procedures, such as by reacting the acyloxy or trifluoroacetoxy derivative with alkali metal hydroxides, e.g., sodium hydroxide or potassium hydroxide.

The hydrolyzed product, 2-oxa-5/3-cyano-ZOfi-hydroxypregnane-3-one, can then be oxidized with Jones reagent (chromium trioxide-sulfuric acid) to yield another end product of this invention 2-oxa-5B-cyanopregnane 3,20- diene.

The following examples illustrate the invention (all temperatures are in degrees Centigrade) EXAMPLE 1 20B-hydroxy-A-norpregn-3-en-2-one A solution of 2.0 g. of A-norprogesterone in 200 ml. of methanol is treated at 0 with 380 mg. of sodium borohydride and stirred at this temperature for one hour. Acetic acid (3 drops) is added and the solution evaporated to dryness, diluted with Water and extracted with chloroform. The chloroform extracts are washed with 8% salt "solution, dried and evaporated. The residue is crystallized from chloroform-isopropyl ether to give 1.68 g. of 2013- hydrxy-A-norpregn-3-en-2-one, M.P. 210-212.

EXAMPLE 2 SB-cyano-205-hydroxy-A-norpregnane2-one A mixture of 300 mg. of ZOB-hydroxy-A-norpregn-B en-2-one, 130 mg. of potassium cyanide and mg. of ammonium chloride in 1 ml. of water and 5 ml. of methanol is refluxed for 70 hours. The mixture is concentrated, diluted with water, and extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried and evaporated. Plate chromatography of the residue on silica gel, using ethyl acetate-chloroform (3:2) as the developing solvent and elution of the most polar band with ethyl acetate gives a residue which is crystallized from ether-isopropyl ether to afford 93 mg. of 5B'cyan0- ZOB-hydroxy-A-norpregnane-2-one, M.P. 188-189. The analytical sample is prepared by recrystallization from 3 chloroform-isopropyl ether, M.P. 189-190; [04 83 (EtOH); A 2.82, 4.49 and 5.74 15 5 5 9.22 3., 18-Me), 8.87 (d, J=6 c./s., 21-310), 8.79 (s, 206-011), 8.62 (s, 19-Me), 7.55 (s, 3-CH and (5.29 (111, 2004-11) Analysis.-Calcd for C H O N (329.47) (percent): C, 76.55; H, 9.48; N, 4.25. Found (percent): C, 76.30; H, 9.27; N, 4.17.

EXAMPLE 3 Sti-cyano-ZOB-acetoxy-A-norpregnane-2-one T33 3 9.33 (5., 18-Me), 8.86 (d, J=6 e./s., 21410 8.63 (IQ-\Ie), 8.00 (s, 20B-acetate) and 7.64 (s, 3-CH EXAMPLE 4 2-oxa-SB-cyano-20 3-trifiuoroacetoxypregnane-3-one A mixture of 400 mg. of 5/3-cyano-2OB-hydroxy-A-norpregnane-2-one and 300 mg. of disodium hydrogen phosphate in ml. of methylene chloride is treated with an excess of peroxytrifluoroacetic acid and stirred at room temperature for 5 days. The mixture is diluted with chloroform and washed with 5% potassium iodide solution, 10% sodium bisulfite solution, dried and evaporated to dryness.

Plate chromatography of the residue on silica gel using chloroform as the developing solvent and elution of the most polar band with ethyl acetate gives a residue which is crystallized from ether-isopropyl ether to yield 138 mg. of 2-oxa-5,8-cyano-20B-trifluoroacetoxypregnane 3 one, M.P. 162-163". The analytical sample is prepared by recrystallization from ether-isopropyl ether, M.P. 166.5 167.5; [aJ +65" (EtOH); )t 4.44, 5.69 and 5.73 T5 45 9.33 5., 18-Me), 8.83 (s, 19-Vle), 8.70 (d, J=s c./s., 21-Me), 7.05 (s, 4"CH2); 5.77 (s, I-CH and 4.97 (In. 2004-11) Analysis.-Calcd for C H F NO (441.50) (percent): C, 62.57; H, 6.85; N, 3.18; F, 12.91. Found (percent): C, 62.49; H, 7.10; N, 3.30; F, 13.26.

EXAMPLE 5 2-oxa-5 3-cyano-20p-acetoxypregn ane-3 -one Following the procedure in Example 4 but substituting 5B-cyano-20fi-acetoxy-A-norpregnane-Z-one for 5,8-cyanofi-hydroxy-A-norpregnane-Z-one, there is obtained the title compound.

EXAMPLE 6 2-oxa-5fl-cyano-20 8-hydroxypregnane-3-one (a) A solution of 100 mg. of 2-oxa-5/3-cyano-20fi-trifiuoroacetoxypregnane-3-one in 8 ml. of dioxane and 13 ml. of 5% sodium hydroxide solution is stirred at room temperature for five hours, acidified with acetic acid and concentrated. Water is added and the aqueous phase is extracted with chloroform. The extracts are washed with 8% salt solution, dried and evaporated to give 2-oxa-5f3- cyano-20B-hydroxypregnane-3-one:

Tgg fi 9.34. 8., ism 8.84 (d., J=6 c./s., 21-110), 8.82 (s., 2ll\'io) and 0.20 (m., 2004-11) (b) Following the procedure in Example 6a, but substituting 2-oxa-5,8-cyano-20(3-acetoxypregnane-3-one for 2- oxa-5fi-cyano-20/3-trifluoroacetoxypregnane-3-one, there is obtained the title compound.

EXAMPLE 7 2-oxa-5B-cyanopregnane-3,20-dione A solution of 180 mg. of 2-oxa-5p-cyano-20/3- hydroxypregnane-3-one in 6 ml. of acetone is treated with a slight excess of chromium trioxide-sulfuric acid. Methanol is added and the mixture is filtered through Hy-flo and evaporated. The residue is plate chromatographed on silica gel using chloroform as the developing solvent. Elution of the major band with ethyl acetate, evaporation and crystallization from acetone-isopropyl gives mg. of 2-oxa- 5B-cyan0pregnane-3,20-dione, M.P. 1505-1515". The analytical sample is prepared by recrystallization from acetone-isopropyl ether, M.P. 151.5-152"; [u] +113 (EtOH);

.gg g,,9.35 18-Me), 8.82 (s, 19mm), 7.88 (s, 21mg 7.03 (s, 4-CH and 5.72 (s, 1-CH Analysis.Calcd for C H NO (343.45) (percent): C, 73.43; H, 8.51; N, 4.08. Found (percent): C, 73.18; H, 8.73; N, 4.17.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound having the formula CN wherein R is hydroxy or acyloxy and wherein the acyl group is derived from a hydrocarbon carboxylic acid of less than thirteen carbon atoms selected from the group consisting of alkanoic acids, alkenoic acids, monocyclic aryl carboxylic acids, monocyclic aryl lower alkanoic acids, cycloalkanecarboxylic acids and cycloalkenecarboxylic acids.

2. A compound in accordance with claim 1 having the name SB-cyano-20,8-acetoxy-A-norpregnane-2-one.

3. A compound in accordance with claim 1 having the name 5,8-cyano-20B-hydroxy-A-norpregnane-2-one.

References Cited UNITED STATES PATENTS 3,271,437 9/1966 Levine 260464 3,330,851 7/1967 Levine et al. 260464 3,346,616 10/1967 Levine et al 260464 3,367,965 2/1968 Levine 260464 X JOSEPH P. BRUST, Primary Examiner US. Cl. X.R.

TED STAS PA @FFR CE'HFIQAE 0F Patent: No, 3,66O 457 Dated May 2,, 1972 Inventor(a) Y Levine It is certified that error appears in the ahove identified patent and that said Letters Patent are hereby untreated as shown below:

Column 1, line 46, "cycloalkylanecarboxylic" should read --cycloalkanecarboxylic- -a Column 2, line 20, "can the be" should read -can then be- Column 2, line 41, "diene" should read -'-dione-- Column 2, line 56, "hydrxy" should read -hydroxy-- Signed and sealed this 19th day ofseptember 197.2o

(SEAL) Attest:

EDWARD M@FLETCHER JR RQBERT GOTTSCHALK Attasting Officer Commissioner of Patents 

